The Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Potential Drug Candidates to Treat Acute Myeloid Leukemia

ABSTRACT Acute myeloid leukemia (AML) is the second most diagnosed and the deadliest subtype of leukemia. Recently genetic loss-of-function studies have demonstrated that a human YEATS domain-containing protein named eleven-nineteen-leukaemia (ENL) functions as a transcriptional coactivator and is essential for the proliferation of AML that harbours oncogenic multiple lineage leukemia (MLL) rearrangements. We previously synthesized a series of small molecule inhibitors ( 1 , 7-9 , 11-15 and 24 ) that displayed significant and specific inhibitory effects against the ENL YEAST domain. In the current work, we report the development of a novel NanoBRET system that allows the analysis of cellular permeability, potency, selectivity, and stability of synthesized ENL inhibitors for their prioritization for further characterizations. Followed by in vitro metabolic stability and cell growth inhibition studies, we narrowed down to a potent and specific ENL YEATS domain inhibitor 13 with both high in vitro metabolic stability and strong anti-proliferation ability on MLL-fusion leukemia cell lines. A mouse pharmacokinetic (PK) analysis showed that at an oral dose of 20 mg/kg compound 13 had 60.9% bioavailability and 2.6 h mean residence time. With these favorable PK characteristics, compound 13 is ready for efficacy studies in an animal model. Cumulatively, the current study has prioritized compound 13 as a promising drug candidate to disrupt the pathogenic functions of ENL for the AML treatment.